JP3490114B2 - Chondroprotectors - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] The present invention relates to a cartilage protective agent.
Specifically, the carboxyl represented by the following general formula (I)
Acid, its cis-trans isomer, its physiologically acceptable
Cartilage protective agent consisting of a salt or an ester thereof
You. [0002] 2. Description of the Related Art Arthrosis includes rheumatoid arthritis and rheumatoid arthritis.
Fever, osteoarthritis, etc. Among them, rheumatoid arthritis
And osteoarthritis have a large number of patients,
Has been considered. Osteoarthritis can be congenital or
Secondary and due to degeneration of articular cartilage due to aging
Some are primary. Primary osteoarthritis has recently become older
It is increasing as the population of the elderly grows. Rheumatoid arthritis
And osteoarthritis have significant differences in etiology and pathology.
You. However, in both cases, joint function is ultimately caused by cartilage destruction.
Are common in that they are obstructed. Rheumatoid arthritis,
Rheumatic fever, systemic lupus erythematosus, osteoarthritis, etc.
The first-line drugs for rheumatic diseases are aspirin,
It is an analgesic and anti-inflammatory agent such as indomethacin. Chronic arthrosis cure
Other therapeutic drugs include gold preparations such as thiosol, immunomodulation
Agents, steroids, D-penicillamine and the like are used. [0003] Caffeic acid, ferulic acid, isoferula
Acid, 3-ethoxy-4-hydroxycinnamic acid, etc.
Such pharmaceutical uses are known. Caffeic acid and fel
Laric acid has antiviral activity (JP-A-4-234319)
There is. Caffeic acid includes calcium antagonists (Japanese Unexamined Patent Publication No.
243822), an antiallergic drug (JP-A-59-1).
Applications such as 55314) are known. Caffeic acid and mosquito
Methyl famate can be used to treat autoimmune diseases (W
O91 / 17749). Also, ferulic acid and isoferula
For acids, immunochemotherapy, drug resistance prevention, anticancer drugs
(JP-A-56-115716)
I have. Ferulic acid also includes hyperlipidemia and platelet aggregation
Applications such as reduced composition (US Pat. No. 4,842,859) are known.
You. Ferulic acid and its esters have anti-inflammatory effects.
(AS Chawla et al., India)
nJ. Exp. Biol. , Vol. 25, no.
3, pp. 187-189, 1987). 3-ethoxy
-4-Hydroxycinnamic acid includes UV absorbers for cosmetics
(Japanese Patent Application Laid-Open No. 64-13018) is known. [0004] SUMMARY OF THE INVENTION However, these
Carboxylic acids, cis-trans isomers, salts thereof, and
And its esters are useful as chondroprotectors
unknown. In addition, the above-mentioned conventional analgesic and anti-inflammatory drugs
It has no effect on cartilage destruction, and
On the other hand, on the contrary, it may worsen. In addition, the chronic
Anti-articular cartilage destruction inhibitory effect is also found in the treatment of arthrosis
Not. The present inventors have proposed a softening technique for suppressing the destruction of articular cartilage.
As a result of intensive research to develop bone protectants, the following general formula
The carboxylic acid represented by (I), its cis-trans variant
Sex, its physiologically acceptable salts, and its esthetics
Is a glycosaminoglyca that makes up the cartilage matrix
(Hereinafter referred to as GAG) is strongly suppressed.
Thus, the present invention has been completed. [0005] SUMMARY OF THE INVENTION Accordingly, the present invention provides
Formula (I): Embedded image (Where R¹And R^TwoAre each independently a hydrogen atom, or
Which is an alkyl having 1 to 6 carbon atoms)
Acid, its cis-trans isomer, its physiologically acceptable
Or its ester (hereinafter referred to as this substance)
And a cartilage protective agent comprising: R¹And R^TwoAmong the charcoal
Preferred examples of the alkyl having 1 to 6 primes are those having 1 to 4 carbons.
Lower alkyl, more preferably methyl,
Tyl, n-propyl, or n-butyl. Of this substance
Configuration of phenyl and carbonyl groups attached to double bond
Are cis-type and trans-type.
Are used for any of the compounds. The physiologically acceptable salts include:
Salts with alkali metals (Na salt, K salt, etc.), alkaline earth
Salt with metal (Ca salt, Mg salt, etc.), Al salt, ammonium
Salt, various amine compounds (primary amine, secondary amine
And tertiary amines). That es
As the ter, aromatic alcohol or aliphatic alcohol
Esters of the aliphatic alcohols
Ter is preferred, and an aliphatic alcohol having 1 to 6 carbon atoms
Are more preferred. Further preferred examples are
, Ethyl, n-propyl, isopropyl, n-butyl
, Isobutyl, t-butyl, n-pentyl, or iso-
It is a pentyl ester. As this substance, for example,
One compound can be exemplified. Both are trans-forms. [0007] [Table 1] ──────────────────────────────────── R¹    R^Two    Ester Name Abbreviation ──────────────────────────────────── H H Caffeic acid CFA Me H Ferulic acid FLA H Me isoferulic acid IFLA EtH3-ethoxy-4-human peroxycinnamic acid 3-EtO-4-HO-CA MeH (Na salt) Sodium ferulate NaFLA Me H Me Methyl ferulate MeFLA MeH Et Ethyl ferulate EtFLA MeH nPr n-propyl ferulate nPrFLA MeH nBu n-butyl ferulate nBuFLA ──────────────────────────────────── Me: methyl, Et: ethyl, nPr: n-propyl, nBu: n-butyl [0008] The main carboxylic acids listed in Table 1 are
Available as a commercial product. For example, caffeic acid is Tokyo Chemical
Ferulic acid and isoferulic acid are sig
Available from the Chemical Company. Also, 3-ethoxy
C-4-hydroxycinnamic acid is 3-ethoxy-4-hi.
Droxybenzaldehyde and malonic acid can be
It is obtained by reacting in the presence of a base (see Example 1). Physiologically acceptable carboxylic acids of the general formula (I)
Salts that can be used include, for example, alkali metals, alkaline earths.
Hydroxides or carbonates of metals, ammonium, etc.
Reaction with carboxylic acid in equimolar amount in a solvent such as water
Can be The ester of a carboxylic acid of the general formula (I)
By reacting an alcohol and a carboxylic acid in the following manner.
Can be 1) Using an appropriate solvent, use an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.
Alternatively, organic acids such as acetic acid and p-toluenesulfonic acid
Alcohol and carboxylic acid in the presence of
Let 2) dicyclohexylcarbodiimide, N, N'-cal
Bonyl di (2-methylimidazole), diphenylkete
-N-cyclohexylimine, alkoxyacetyl
, Polyphosphoric acid ethyl ester, thionyl chloride, oxyl chloride
In the presence of a condensing agent such as salyl, dimethylformamide,
Acetone, dioxane, acetonitrile, chloroform
, Ethylene chloride, tetrahydrofuran, pyridine, etc.
In an organic solvent, an alcohol is reacted with a carboxylic acid.
You. Usually performed under cooling or at room temperature. 3) Tricarboxylic acid anhydride and alcohol
Basic substances such as pyridine, pyridine, methylethylpyridine, etc.
React in the presence. 4) Carboxylic acid halide (acyl halide: chloride)
Product, bromide, etc.) and alcohol with triethylamine,
Add basic substances such as lysine and methylethylpyridine.
In a solvent or a basic solvent such as pyridine.
You. The toxicity of this substance is as described below.
Therefore, this substance is a very safe compound. (1) Acute toxicity of caffeic acid LDLO (minimum lethal dose) by intraperitoneal administration in rats
1500 mg / kg. (Toxicology
and Applied Pharmacology,
Vol. 36, p. 227, 1976) (2) Ferulic acid, isoferulic acid and 3-ethoxy-
Acute toxicity of 4-hydroxycinnamic acid Using ddY strain male mice (5 mice per group), 400 mg /
Observation was made for one week after oral administration of kg. Oral administration is above
Each test substance was treated with 0.3% CMC (carboxymethyl
Lulose) and 0.05% Tween 80 (Polyoxy
Ethylene sorbitan monooleate, Tokyo Chemical Industry Co., Ltd.
Is dispersed in an aqueous solution of
Gave. There were no deaths for any of the test substances,
No abnormalities were found in weight or general condition. Ferulic acid
Sodium, methyl ferulate, ethyl ferulate,
The same applies to propyl ferulate and butyl ferulate.
there were. In addition, methyl ferulate and isoprolate
LD by intraperitoneal administration of pill in mice₅₀Values are 1 each
188.5 mg / kg and 1059.2 mg / kg
You. (AS Chawla et al., Indi.
an J. Exp. Biol. , Vol. 25, no.
3, pp. 187-189, 1987) This substance has a pharmacological effect on cultured chondrocytes.
Inhibition of cartilage destruction in rabbit (shoulder and knee joint chondrocytes)
(See Example 2 described later). However, the place of ester
In this case, the effect is not clear in the in vitro experiment. this
Even in animal experiments on mouse air cyst models
Showed an inhibitory effect on cartilage destruction. Therefore, this substance
Is used to treat various types of arthropathy with joint cartilage destruction.
Useful as a bone protectant. Examples of such arthropathy are
Rheumatoid arthritis, osteoarthritis, shoulder periarthritis, neck and shoulder
Arm syndrome, low back pain, etc. Formulation of a chondroprotectant containing the substance as an active ingredient
The form may be a general form. This substance alone or genuine
Any mixture of quality and a pharmaceutically acceptable carrier or diluent
However, it can be used as a preparation. The amount of the active ingredient in the formulation,
0.01 to 100% by weight, preferably 0.1 to 70% by weight
%. The chondroprotective agent of the present invention can be administered orally or parenterally.
Can also be administered. The dose of the chondroprotective agent of the present invention
(Animal or human), age, individual differences, medical condition, etc.
In some cases, a dose outside the following range may be administered. But
In general, when targeting humans, the oral dose of this substance
Is 0.1 to 500 mg / kg (body weight) per day,
Preferably, it is 0.5 to 200 mg / kg (body weight). Through
Usually, the daily dose is administered once or in 2 to 4 divided doses. [0014] The present invention will be described below in detail with reference to examples.Example 1: Synthesis of this substance (1) Synthesis of 3-ethoxy-4-hydroxycinnamic acid Malonic acid (1.56 g) and pyridine (3.0 ml)
Into a flask (100 ml). To this, 3-d
Toxic-4-hydroxybenzaldehyde (1.66
g) and aniline (30 μl) and added at 55 ° C. for 3 hours
Reacted. Dilute sulfuric acid was added to this reaction solution to make it acidic.
Thereafter, filtration was performed to obtain a crude crystal. After washing these crystals with water,
Dry to give the title compound (1.1 g, 56.1%)
Obtained as yellow crystals. Melting point: 157-158 ° C¹ H-NMR (CDCl_Three, Δ ppm): 1.40
(T, 3H, J = 6.87Hz, CH_Three), 4.19
(Q, 2H, J = 6.87Hz, CH_Two), 6.36
(D, 1H, J = 16.04 Hz), 6.87 (d, 1
H, J = 8.2 Hz), 7.13 (dd, 1H, J =
8.2, 1.8 Hz), 7.31 (s, 1H), 7.5
9 (d, 1H, J = 16.04 Hz) IR spectrum (cm^-1): 3550s, 2980s,
2900s, 2830s, 2700m, 2600m, 2
550m, 2510m, 1675s, 1625s, 15
90s, 1515s, 1482m, 1435m, 141
5m, 1330m, 1290s, 1260s, 1235
s, 1195s, 1165s, 1121s, 1035s (2) Synthesis of methyl ferulate Ferulic acid (4.85 g) was added to an eggplant-shaped flask (200 m
l) and contain methyl alcohol containing hydrogen chloride (4%).
Then, the mixture was heated and refluxed for 1 hour. T
LC (n-hexane / ethyl acetate = 2/1)
After confirming the loss, use a rotary evaporator under reduced pressure.
The solvent was distilled off. Add benzene to the residue and again
The solvent is distilled off using a re-evaporator to obtain a crude product.
Was. This crude product is purified by silica gel column chromatography.
ー (φ5.5 × 7.0cm, 60g; n-hexane / vinegar)
(Ethyl acetate = 2/1) to give the title compound.
Was. Crystallization from n-hexane gave white crystals (5.09).
g, 97.9%). Melting point: 63-64 ° C¹ H-NMR (CDCl_Three, Δ ppm): 3.79
(S, 3H, COOCH_Three), 3.90 (s, 3H, O
CH_Three), 6.08 (s, 1H, OH), 6.28
(D, 1H, J = 15.6 Hz, H3), 6.91
(D, 1H, J = 8.25 Hz), 7.01 (d, 1
H, J = 1.74 Hz), 7.04 (dd, 1H, J =
8.25, 1.74 Hz), 7.62 (d, 1H, J =
15.6Hz, H4) (3) Synthesis of ethyl ferulate Ferulic acid (4.85 g) was added to an eggplant-shaped flask (200 m
l) and put in ethyl alcohol containing hydrogen chloride (4%).
(50 ml) and heated to reflux for 2.5 hours.
Was. Original by TLC (n-hexane / ethyl acetate = 2/1)
After confirming that the charge has disappeared, rotate the evaporator under reduced pressure.
The solvent was distilled off with a filter. Add benzene to the residue and again,
The solvent is distilled off using a rotary evaporator and the wine red
A crude product of color (5.79 g) was obtained. This crude product is
Ricagel column chromatography (φ5.5 × 7.0)
cm, 60 g; n-hexane / ethyl acetate = 3/1)
Separate and purify the title compound (5.06 g, 91.2%)
Got. Crystallized from n-hexane to give white crystals (4.
743 g, 85.3%). Melting point: 41-43 ° C¹ H-NMR (CDCl_Three, Δ ppm): 1.33
(T, 3H, COOCH_TwoCH_Three), 3.91 (s, 3
H, OCH_Three), 4.25 (q, 2H, J = 7.33H)
z), 6.06 (s, 1H, OH), 6.28 (d, 1
H, J = 15.6 Hz), 6.91 (d, 1H, J =
6.8 Hz), 7.02 (s, 1H), 7.06 (d,
1H, J = 8.25 Hz), 7.61 (d, 1H, J =
15.6Hz) (4) Synthesis of n-propyl ferulate Ferulic acid (4.85 g) was added to an eggplant-shaped flask (200 m
l) and n-propyl containing hydrogen chloride (4%)
Add alcohol (50 ml) and heat to reflux overnight.
Was. Original by TLC (n-hexane / ethyl acetate = 2/1)
After confirming that the charge has disappeared, rotate the evaporator under reduced pressure.
The solvent was distilled off with a filter. Add benzene to the residue and again,
The solvent is distilled off using a rotary evaporator to obtain the crude product.
Got. This crude product is subjected to silica gel column chromatography.
Feet (φ5.5 × 7.0 cm, 60 g; n-hexane
/ Ethyl acetate = 2/1).
(5.48 g, 91.6%) as a colorless oil.
Was.¹ H-NMR (CDCl_Three, Δ ppm): 0.99
(T, 3H, J = 7.33 Hz), 1.72 (s, 2
H, J = 7.33 Hz), 3.90 (s, 3H, OCH)
_Three), 4.16 (t, 2H, J = 6.9 Hz), 6.1
1 (s, 1H, OH), 6.30 (d, 1H, J = 1
5.6 Hz), 6.91 (d, 1H, J = 8.25H)
z), 7.02 (s, 1H), 7.05 (dd, J =
8.23 Hz), 7.61 (d, 1H, J = 15.6H)
z) (5) Synthesis of n-butyl ferulate Ferulic acid (5g) in eggplant type flask (200ml)
N-butyl alcohol containing hydrogen chloride (4%)
(50 ml), and the mixture was heated under reflux for about 2 hours. T
LC (n-hexane / ethyl acetate = 2/1)
After confirming the loss, use a rotary evaporator under reduced pressure.
The solvent was distilled off. Add benzene to the residue and again
The solvent is distilled off using a re-evaporator to obtain a crude product.
Was. This crude product is purified by silica gel column chromatography.
-(Φ5.5 × 8.5cm, 70g; n-hexane / vinegar)
(Ethyl acetate = 3/1).
(25 g, 99%) as a colorless oil.¹ H-NMR (CDCl_Three, Δ ppm): 0.96
(T, 3H, J = 7.33 Hz), 1.44 (seq,
2H, J = 7.33 Hz), 1.68 (quint, 2
H, J = 6.88 Hz), 3.91 (s, 3H), 4.
21 (t, 2H, J = 6.88 Hz), 6.04 (s,
1H, OH), 6.29 (d, J = 16.0 Hz, 1
H), 6.91 (d, J = 8.25 Hz), 7.02
(S, 1H), 7.05 (dd, J = 8.25 Hz) [0019]Example 2: Cartilage destruction in cultured chondrocytes
Inhibiting action a) Preparation of cultured chondrocytes Rabbit (New Zealand White White Rabb)
it) (weight 1-1.5kg, purchased from Kitayama Labes)
Cartilage was aseptically removed from the shoulder and knee joints. This is PB
S (Ca²⁺, Mg²⁺Free), Hanks, and 0.1%
After washing well with EDTA-PBS, chop into about 1 mm square
It is. To this, PBS containing 0.1% EDTA (Ca²⁺, M
g²⁺Free) and treat in a thermostat at 37 ° C for 30 minutes.
Was. Further, at 37 ° C. with a trypsin solution (0.25%).
For 1 hour to remove connective tissue attached to cartilage
Was. Next, after removing the supernatant, the cartilage was replaced with fetal bovine serum (FB).
S) Ham containing 10% and 0.2% collagenase
  Treated in F-12 medium for about 2-2.5 hours.
The collagenase solution was centrifuged (1500 rpm).
m. ), And a ham medium containing 10% FBS (cartilage)
Medium), and finally chondrocytes, cartilage
3 × 10 in medium^Five Cells / ml
Was adjusted to 1 ml of this dispersion is placed in a 24-well plate
Within 2 weeks after seeding and reaching confluence 4 days later
Were subjected to the experiment. B) Addition of test substance and cartilage destruction factor Remove the cartilage medium used previously for chondrocyte culture.
Serum-free S-Clone medium
Add 800 μl (containing 0.1% human serum albumin)
Then, add 100 μl of the test substance solution (10 times the final concentration).
S-Clone medium solution, DMSO concentration 2.5%)
In the presence of carbon dioxide (5%) and air (95%)
After culturing for 2 hours, the cartilage destruction factor PMA
Lumiristate acetate) (final concentration 0.1 μg / m
l) or interleukin 1α (IL-1α) (final
(Concentration: 20 u / ml) was added to the chondrocyte culture. The test substances used here are as follows:
You. This substance: caffeic acid (CFA; Tokyo Chemical Industry Co., Ltd.)
Company), Ferulic acid (referred to as FLA; Sigma Chemical
And 3-ethoxy-4-hydroxycinnamon
Acid [noted as 3-EtO-4-HO-CA; synthesized in Example 1 (1)
Compound] Comparative substance: Indomethacin (Sigma Chemical Company)
-) C) Quantification of GAG Two days later, after removing the chondrocyte culture supernatant, the remaining cartilage was removed.
Add 1 ml of 0.03% papain solution to the matrix layer.
And reacting at 65 ° C. for 1 hour,
AG was released. GAG in treated papain solution
The weight was determined using the 1,9-dimethylmethylene blue method.
(Quantitative method: RW Farndale, Bioc
him. Biophys. Acta. , Vol. 88
3, pp. 173-177, 1986). Cartilage destruction
In the cartilage matrix of the control group
GAG of each sample when GAG content is 100
The relative amount was determined by the following equation. Contains GAG for control
The amount is used for experiments after the chondrocytes reach confluency
A certain width (28.0-7
4.5 μg / ml). [0023] ## EQU1 ## GAG relative amount% = (B / A) × 100 A: Includes GAG in the group without cartilage destruction factor (control)
Heavy B: cartilage destruction factor added group or (cartilage destruction factor + test substance
Quality) GAG content of added group The results are shown in Tables 2 and 3. GAG contained in the table
Quantities are mean ± standard error (n = 3). Each experiment
About control and cartilage destruction factor added group
Was. The significant difference test was performed for the cartilage destruction factor-added group in each experiment.
The test was performed by Student's t-test. Test
The display of the result is as follows. *: P <0.05, *
*: P <0.01, ***: P <0.001. Cartilage destruction
For the GAG content of the factor-free group (control)
And add cartilage destruction factors PMA and IL-1α
This induced a decrease in GAG. Under this condition
Therefore, this substance suppresses the decrease of GAG and acts to suppress cartilage destruction.
It was confirmed that it had a use. In contrast, conventional
Indomethacin, a pain and anti-inflammatory drug, is a
No use was observed, and conversely, the effect of promoting cartilage destruction was observed. [0025] [Table 2] ───────────────────────────────────  Sample name GAG content μg / ml (GAG relative amount%) ───────────────────────────────────  Control 43.2 ± 1.5^**  (100)  IL-1α 33.4 ± 1.0 (77.3)   IL-1α + FLA (100 μM) 39.9 ± 0.8^**  (92.4)   IL-1α + CFA (100 μM) 40.9 ± 0.7^*** (94.7) -------------------------------------------------- -------------------  Control 43.4 ± 1.7^**  (100)  PMA 32.1 ± 1.6 (74.0)   PMA + FLA (100 μM) 41.1 ± 4.2 (94.7)   PMA + CFA (100 μM) 47.7 ± 1.5^*** (110) -------------------------------------------------- -------------------  Control 74.5 ± 0.6^**  (100)  PMA 46.2 ± 0.8 (62.0)  PMA + 3-EtO-4-HO-CA (100 μM) 61.5 ± 0.4^*** (82.6) ─────────────────────────────────── [0026] [Table 3] ───────────────────────────────────  Sample name GAG content μg / ml (GAG relative amount%) ───────────────────────────────────  Control 28.0 ± 0.7^*** (100)  PMA 15.4 ± 0.5 (55.0)  PMA + indomethacin (10 μM) 13.2 ± 0.6^*   (47.1)                     (33 μM) 11.7 ± 0.8^**  (41.8) ─────────────────────────────────── [0027]Example 3: In mouse air cyst model
Cartilage destruction inhibitory action The test method is described in K. M. K. Bottomley et
al. , Br. J. Pharmacol, Vol. 9
3, pp. 627-635 (1988).
Method. S. D. Strain rat (5.5 weeks old, female)
Aseptically, 40-50 mg of femoral head cartilage (Fem
oral Head Cartridge; written as FHC
) And take out a 5mm square (weight about 3mg) cot
After wrapping, BALB / c mice (7 weeks old, female)
Implanted subcutaneously on the back (5 ml of air injected the day before).
From the third day of implantation, n-ferulic acid was added 5 times a week.
Ropyl [nPrFLA; synthesized in Example 1 (4)
Compound; each dose of 100 mg / kg]
A mixed aqueous solution of Tween 80 (final concentration: CMC;
0.3%, Tween80; 0.05%)
It was administered orally. The control group contained the above CMC and Tw
Only the mixed aqueous solution of een80 was orally administered. Embedding
Take out the embedded FHC on day 21 and dissolve papain
Solution (4 u / ml, 0.05 M PBS, pH 6.5, 1
0 ml) to degrade the FHC matrix. After disassembly,
The GAG content in the papain solution was adjusted to 1,9-dimethylene
It was quantified using the blue method (quantitation method: RW Farn
dale, Biochem. Biophys. Act
a. , Vol. 883, pp. 173-177,198
6). For the untreated group, FH on day 3 of implantation
C was removed and the GAG content was measured. The results are shown in Table 4. GAG content in table /
FHC is the average of the GAG content per FHC ±
This is the value of the standard error (n = 8 to 10). GAG relative amount%
Means that the GAG content / FHC of the untreated group is 100
Is the relative amount of Formed around the implanted FHC
Granulation secretes cartilage destruction factor. For this reason,
In the roll group, a decrease in GAG was observed. On the contrary,
In the group to which this substance was administered, reduction of GAG reduction was observed.
The effect of inhibiting cartilage destruction was confirmed. In addition, methyl ferulate
, Ethyl ferulate, and n-butyl ferulate
The same tendency as n-propyl ferulate
Was. [0029] [Table 4] ────────────────────────────────────   Treatment method GAG content / FHC μg / FHC 1 piece (GAG relative amount%) ────────────────────────────────────   No treatment 745.8 ± 24.5 (100)   Control 387.1 ± 17.1 (51.9)   nPrFLA 435.3 ± 26.4 (58.4) ──────────────────────────────────── [0030]Example 4: Formulation example (granules)         Ferulic acid 20 parts by weight         Lactose 68 parts by weight         Low substituted hydroxypropyl cellulose 10 parts by weight         Hydroxypropyl cellulose 2 parts by weight And then use 32 parts by weight of wetting agent ethanol.
And kneaded. Then perform wet granulation, dry and granulate
Got. [0031] The substance constitutes a cartilage matrix
It strongly suppresses the decrease of GAG and shows a cartilage protective action. or,
Low toxicity. Therefore, this substance, as a cartilage protective agent,
Rheumatoid arthritis, osteoarthritis, shoulder periarthritis, neck and shoulder
Extremely useful application for the treatment of arthropathy such as arm syndrome and low back pain
Having.

──────────────────────────────────────────────────続 き Continued on the front page (56) References Bert A. 't Hart, Biotechnology Therapeutics, 1992, 3 (3 & 4), 119-135, J. Biol. Cyong et al. , A cuputure & Electro-Therapeutics Res. , Int. J. 1982, Vol. 7,173-201 (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/00-31/80 A61P 29/00 A61P 19/02 JICST file (JOIS) CAPPLUS (STN) MEDLINE (STN) REGISTRY (STN)

Claims (1)

(57) [Claims 1] The general formula (I): (Wherein R ¹ and R ² are each independently a hydrogen atom or an alkyl having 1 to 6 carbon atoms), a cis-trans isomer thereof, a physiologically acceptable salt thereof Or a chondroprotective agent comprising the ester thereof.